ctDNA Generates Momentum in Adjuvant Stage II/III Colon Cancer Setting

Although circulating tumor DNA (ctDNA) is in earlier stages of investigation for resected colon cancer, it has the potential to aid in accurately predicting the risk of recurrence, which is a challenge as there are no prospectively validated biomarkers from randomized studies available in this setting to determine whether adjuvant chemotherapy is necessary.¹ The overtreatment of patients who may have been cured from surgery can also result in the adjuvant setting, according to John L. Marshall, MD.

“ctDNA is the closest thing we have to something that will change [the way we treat patients],” Marshall said in an interview with OncologyLive. “It’s all about the precision medicine piece of things, being able to identify appropriate genetic markers and use those markers to identify who should be treated, what therapies to use, [and] predictors of risk—this ranges now from screening through metastatic disease.” Marshall is chief of the Division of Hematology and Oncology, a professor of medicine and oncology, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Given that more than 30% of patients with resectable colorectal cancer (CRC) will experience disease recurrence following surgery and adjuvant chemotherapy, there is great interest in using the presence of ctDNA in plasma after treatment to predict recurrence, as it has been shown to be a strong prognostic factor.²

Findings from a large post hoc analysis of the phase 3 IDEA-France (NCT00958737) and IDEA-Greece (NCT01308086) trials revealed that at a median follow-up of more than 80 months, ctDNA was the most significant prognosticator for disease recurrence (adjusted HR, 5.21; P < .001) and death (adjusted HR, 4.81; P < .001) in patients with stage III colon cancer; the multivariable analyses adjusted for major prognostic factors in this patient population.³

Data also showed that ctDNA was prognostic in patients with stage III high- and low-risk disease and in those treated with 3 and 6 months of adjuvant chemotherapy. The prognostic value of the Immunoscore assay was also evaluated and showed discriminant outcomes in patients who were ctDNA negative. In patients with both ctDNA-negative and Immunoscore-high results, the 5-year time to recurrence rate was greater than 90%.

“We have studies, and others are starting to have studies, looking at patients who are ctDNA positive after adjuvant therapy and what to do,” Marshall said. “The National Comprehensive Cancer Network guidelines still have not formally recommended doing ctDNA testing, and yet lots of us are [testing ctDNA]. The question is, how do you use this information to help the patient? The criticism from the guidelines is that you don’t know what to do with it if you have a positive test, and we’re trying to figure out, as quickly as we can, how to incorporate that [into treatment].”

The observational BESPOKE CRC study (NCT04264702), which was presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, was the first large, prospective, US-based trial that reported data examining the utility of tumor-informed ctDNA in the adjuvant setting for patients with CRC. Findings from the interim analysis of the prospective, multicenter study revealed that ctDNA positivity during surveillance was prognostic of outcomes irrespective of whether patients with stage II to III CRC received adjuvant chemotherapy.⁴

Additionally, ctDNA­ positivity at the minimal residual disease (MRD) time point was predictive of inferior disease-free survival (DFS) outcomes. Patients who were MRD positive (n = 93) experienced a 2-year adjuvant DFS rate of 29.86% (95% CI, 13.26%-48.54%) compared with 91.59% (95% CI, 88.38%-93.94%) among patients who were MRD negative (n = 530). The median DFS post surgery was 15.98 months (95% CI, 13.77-20.22) vs not reached (NR), respectively (HR, 12.1; 95% CI, 8.0-18.3; P < .0001).

Furthermore, the benefit from adjuvant chemotherapy was only observed in patients who were MRD positive. Patients who had MRD-positive disease and received adjuvant treatment (n = 85) experienced a median DFS post surgery of 17.78 months (95% CI, 14.37-NR) vs 7.52 months (95% CI, 3.52-15.88) among those who underwent observation as adjuvant treatment (n = 100; HR, 3.06; 95% CI, 1.43-6.56; P = .0025).

“We have ctDNA [and] MRD testing to decide about adjuvant therapy, and studies are ongoing there,” Marshall noted. “Sorting colon cancer into its different genetic subtypes is critical. We’re looking at the role of MRD [with] ctDNA testing in treatment, optimizing immunotherapy in those who have microsatellite-unstable disease, [and] trying to develop immunotherapy for those who aren’t, so that’s in both directions.”

Avoiding Overtreatment in the Adjuvant Setting

“Tissue-based testing and pure blood-based testing are of different quality, sensitivity, [and] specificity, but the reason to do [them] is that we dramatically overtreat [patients] with adjuvant therapy,” Marshall said. “Most of the patients we give adjuvant therapy to are already cured. Could we figure out who those patients are and not worry about exposing them to chemotherapy that they don’t need in the first place?”

The prospective phase 2/3 CIRCULATE-NORTH AMERICA study (NRG-GI008; NCT05174169) is active and currently enrolling patients with colon cancer to evaluate the role of ctDNA presence in risk stratification for either escalation or de-escalation of adjuvant therapy. Additionally, investigators plan to combine aggregate data with that from CIRCULATE-JAPAN.¹

“One [consideration] is selection of patients who need therapy, and the world is doing studies to try and figure that out,” Marshall noted. “But the second piece is, what if patients are still positive after you’ve done whatever [treatment] you were going to do? This is an emerging field that we and others are leading to try and identify therapies that potentially could intervene then, instead of waiting until the patient has obvious metastatic disease.”

Data from CIRCULATE-JAPAN, which is part of the larger GALAXY trial (UMIN000039205), showed that ctDNA-based MRD is both a prognostic and predictive tool across different actionable biomarkers in CRC, suggesting that there is potential for integration of MRD-driven targeted treatments in this patient population. DFS by ctDNA positivity and actionable biomarkers, including the BRAF V600E mutation and ERBB2 amplification, were examined in the trial. Patients with a BRAF V600E mutation experienced a 24-month DFS rate of 87.9% (95% CI, 81.0%-95.4%) if they were ctDNA negative (n = 165) compared with not available for patients who were ctDNA positive (n = 10; HR, 201.40; 95% CI, 38.33-2080.89; P < .0001). Among patients with an ERBB2 amplification, the 24-month DFS rates were 83.0% (95% CI, 70.4%-97.9%) for those who were ctDNA negative (n = 33) vs 16.3% (95% CI, 4.7%-57.3%) for those who were ctDNA positive (n = 14; HR, 9.18; 95% CI, 3.18-29.90; P < .0001).⁵

When asked about ongoing studies demonstrating promise in the adjuvant setting, Marshall noted, “It’s all early, so to say particularly promising is too strong. The bigger studies are just trying to prove the principle of the thing. To me, the exciting stuff is then, what do you do [treatment-wise]? How do you intervene on it? That’s still fairly early.”

The clinical validation study CORRECT-MRD I (NCT06398743) is recruiting patients with the primary objective of validating the association of postdefinitive therapy and prerecurrence follow-up cDNA positivity with recurrence-free interval. The trial had enrolled 233 of the anticipated 400 patients as of July 10, 2024, and will examine recurrence-free interval as the primary end point in patients with stage II to III CRC.²

Beyond Biomarkers and ctDNA: New Adjuvant Therapies Are Critical

“Our discoveries in metastatic disease have not necessarily translated over to the adjuvant setting. We are pushing hard to try and identify new therapies we could bring to the table instead of just using the old ones a bit better. We need new therapies,” Marshall said. “We have failed to make significant advances compared with other cancers [as] we are still giving the same adjuvant therapy that we have been giving for 20 years, and there is no other cancer where that’s true. The reason to come to the 10th Annual School of Gastrointestinal Oncology^® [SOGO] conference is that it falls on us to accelerate our understanding and the research. We’ll be talking about where we are today and how to move [the field] forward at the meeting.”

Joining Marshall as cochair of SOGO is E. Gabriela Chiorean, MD, of Fred Hutch Cancer Center in Seattle, Washington. SOGO, slated for February 15, 2025, in Pasadena, California, will also detail precision medicine and the latest advancements regarding ctDNA and more.⁶

“We need to start over again is the answer. You’re asking me to bet on a horse—I’m not going to bet on a horse,” Marshall said on whether a therapy has the potential to best chemotherapy in the adjuvant setting. “We don’t know some of the basics [on] even how to start the horse race over again, and I believe that’s part of the reason we have languished.”

References

1. Dasari A, Yu G, Kopetz S, et al. Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA): NRG-GI008. J Clin Oncol. 2024;42(suppl 16):TPS3641. doi:10.1200/JCO.2024.42.16_suppl.TPS3641
2. Tsukada Y, Sagawa T, Srinivasan G, et al. CORRECT-MRD I: a clinical validation study to predict recurrence in stage II-III colorectal cancer (CRC) using a bespoke circulating tumor DNA (ctDNA) assay to detect molecular residual disease (MRD). J Clin Oncol. 2024;42(suppl 23):TPS98. doi:10.1200/JCO.2024.42.23_suppl.TPS98
3. Taieb J, Souglakos I, Boukovinas I, et al. Combined analyses of ctDNA and Immunoscore in stage III colon cancer patients: a post hoc analysis of the IDEA-France and -Greece trials. Ann Oncol. 2024;35(suppl 1):S5. doi:10.1016/j.annonc.2024.05.018
4. Kasi PM, Aushev VN, Ensor J, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): interim analysis of BESPOKE CRC study. J Clin Oncol. 2024;42(suppl 3):9. doi:10.1200/JCO.2024.42.3_suppl.9
5. Nakamura Y, Watanabe J, Hirata K, et al. Prognostic and predictive value of ctDNA-based MRD and actionable biomarkers in patients with resectable colorectal cancer: CIRCULATE-Japan GALAXY. J Clin Oncol. 2024;42(suppl 16):3609. doi:10.1200/JCO.2024.42.16_suppl.3609
6. 10th Annual School of Gastrointestinal Oncology (SOGO). Physicians’ Education Resource, LLC. Accessed September 19, 2024. bit.ly/3TzHMag